1. Field of the Invention
The present invention provides novel nitroxides which are effective as LDL lowering agents and which also have antioxidant capacity.
2. Description of the Art
It is generally recognized that high blood cholesterol levels are significant risk factors in cardiovascular disease.
It has been established that 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the first rate limiting enzyme in the biosynthetic pathway for cholesterol, that inhibition of HMGR activity results in a decrease in serum total cholesterol and low density lipoprotein (LDL) cholesterol levels, and that a decrease in serum LDL-cholesterol levels is reflected in a reduction of plasma level of apolipoprotein B. (Brown, et al, J. Lipid Res, 21: 505-517 (1980)).
Tocotrienols have been shown to suppress HMGR resulting in the inhibition of cholesterol biosynthesis and a subsequent drop in LDL cholesterol, apolipoprotein B, thromboxane B.sub.2, platelet factor 4 and glucose levels. (Wright, et al, A Symposium On Drugs. Affecting Lipid Metabolism, Houston, Tex. (November 1989)).
The tocotrienols are structurally related to the tocopherols (vitamin E) and differ only by possessing unsaturation in the isoprenoid side chain. Like the tocopherols, the tocotrienols have antioxidative activity. (Yamaoka, et al, Yukagaku, 3.4: 120-122 (1985); Serbinova, et al, Free Radical Biology and Medicine, 10: 263-275 (1991)).
Active oxygen species are known to play pivotal roles in the genesis of atherosclerotic plaques, thrombotic episodes, ischemic damage, cancer, aging, dementia, and inflammatory conditions. (Sies, H., Oxidative Stress; Academic Press, New York, (1985); Santrucek, M., Krepelka, J., Drugs of the Future, 13: 973-996 (1988); Steinberg, Circulation, 84: 1400-24 (1991)). Of particular interests are the potential protective effects of antioxidants on lipoproteins, since oxidized LDL is thought to be atherogenic. (Buckley et. al., Drugs, 37: 761-800 (1989); Gwynne et. al., Am. J. Cardiology, 62: 1B-77B (1988)).
PROBUCOL (4,4'-[(1-methylethylidene)bis(thio)]bis[2,6-bis(1,1-dimethylethyl)] (Lorelco, Marion Merrell Dow) (Formula I) is a hypolipidemic drug, which is also an excellent antioxidant. PROBUCOL inhibits the oxidative modification of LDL both in vitro and in vivo. (Steinberg, Am. J. Cardiol., 57: 16H-21H (1986)). PROBUCOL, however, suffers from bioavailability problems, exhibits only modest reductions in LDL cholesterol, and has undesirable effects on HDL cholesterol. ##STR1##
Esterbauer et al. (Dieber-Rotheneder, et al., J. Lipid Res., 2: 1325-32 (1991)) have examined the oxidative resistance of LDL as a function of oral vitamin E supplementation. While the oxidative resistance of LDL was significantly enhanced during vitamin E supplementation, antioxidant effectiveness varied considerably from subject to subject.
Nitroxides have been used for years as spin labels for probing the structure of biological membranes. Recently, the capacity of nitroxides to function as superoxide dismutase (SOD) mimetics has gained attention in the literature. (Samuni, et al., J. Biol. Chem., 263: 17921-24 (1988) and Mitchell, et al., Biochemistry, 29: 2802-2807 (1990)). An international patent application has been filed by Pharmacia AB for the use of low molecular weight nitroxides as antiischemic agents (myocardial)(PCT/SE87/00629). The metabolic pathways of nitroxides have been recently reviewed (Schwartz, Free Rad. Res. Comms., 9: 399-405 (1990)). Nitroxides are readily reduce in vivo to give hydroxylamines, which are in turn capable of oxidation back to nitroxides. This redox transfer is mediated by enzymatic pathways in the mitochondria. The nitroxide/hydroxylamine shuttle has interesting implications for the design of lipid peroxidation inhibitors (Nilsson, et al., J. Biol. Chem., 264: 11131-35 (1989) and Nilsson, et al., Chem.-Biol. Interactions, 74: 325-42 (1990).
While the causative factors in the development of atherosclerosis are many, two important ones are elevated serum cholesterol levels and excessive LDL oxidation.
The present invention provides novel compounds which maximize cholesterol biosynthesis inhibition and antioxidant efficiency within the same molecule. The compounds of the present invention generally have greater bioavailability and antioxidant capacity than PROBUCOL.